Neurogenesis occurs throughout life, particularly in the hippocampus, and the balance of neuronal loss and birth is essential in generating the plasticity necessary for new memory formation. In the adult mammalian hippocampus, production of new neurons is influenced by a variety of environmental and behavioral conditions. Factors that have been described as influencing neurogenesis, include, for example, exercise, diet, environmental stimulation, steroids, electroconvulsive therapy, and antidepressants. These findings have stimulated great interest in determining if hippocampal activity itself meaningfully guides neurogenesis, thereby implementing a novel form of network plasticity at the cellular level that would go beyond the well-known forms of plasticity that occur at the synaptic level. Insertion of new neurons could modulate the capability of the adult hippocampal network to handle storage of new memories or clearance of old memories. Furthermore, linking neurogenesis to neuronal activity might adapt the adult network both to physiological demands and to pathological insults.
The generation of new neurons within the hippocampus is mediated by proliferating neural stem/progenitor cells, which are highly sensitive to local signaling. Stem cells represent the most immature cell necessary for neurogenesis. These cells give rise to more restricted precursors or progenitor cells and ultimately these progenitors differentiate into new functional neurons. These cells produce neurons in response to signals received from surrounding cells as well as humoral signals from circulating hormones, cytokines, and growth factors. Gross alterations in local microenvironments may allow ectopic neurogenesis to occur, or even block essential neurogenesis, leading to deficits in neurogenesis-dependent functions, such as learning and memory.
There are numerous diseases associated with neurodegeneration. For example, Parkinson's disease is associated with a loss of dopaminergic neurons in certain brain regions. Alzheimer's Disease is characterized by the death of nerve cells in regions of the brain involved in language and memory. In addition, aging may be associated with a decrease in synaptic plasticity, which leads to a reduction in memory. Other neurodegenerative diseases include Huntington's chorea and amyotrophic lateral sclerosis (Lou Gehrig's disease). Mild cognitive impairment (MCI) that afflicts millions of Americans over the age of 45, unrelated to frank dementia or Alzherimer's disease, may also be related to neuronal loss.
Trauma is also a cause of neural damage. Traumatic brain injury (TBI) can significantly affect many cognitive, physical, and psychological skills. Physical deficit can include ambulation, balance, coordination, fine motor skills, strength, and endurance. Cognitive deficits of language and communication, information processing, memory, and perceptual skills are common. Brain injury can occur in many other ways, including accidents in which the head strikes an object, insufficient oxygen as occurs during strokes, poisoning, or infection.
Altered neuron number in the brain, in particular within the hippocampus, may also occur during mental illnesses such as depression, anxiety disorders, schizophrenia, and autism. For example, the hippocampus tends to be smaller in humans suffering from depression, anxiety disorders such as PTSD, and schizophrenia, and neuron number may be increased in autism. Furthermore, many clinically efficacious anti-depressant medications enhance neurogenesis in the hippocampus.
There is a need to develop compounds and methods of treatment that prevent the onset, and/or ameliorate the symptoms, of diseases associated with damage, dysfunction, or degeneration of neurons. There is also a need to develop compounds and methods of treatment to improve the regeneration and repair of neurons in the brain. Preferably, the treatment will allow for controlled neurogenesis to replace damaged neurons, or to prevent the loss of neurons. Compounds that prevent or reduce neurodegeneration may be used to prevent a variety of diseases, or may be used to specifically target one disease or brain region.
Publications
Aspects of neurogenesis are disclosed, for example, in Deisseroth et al. (1996) Neuron 16, 89-101; Deisseroth et al. (1998) Nature 392, 198-202; Deisseroth et al. (2003) Curr Opin Neurobiol. 13, 354-65; Monje et al. (2002) Nat Med 5, 5; Palmer et al. (1999) J Neurosci 19, 8487-8497; Palmer et al. (1997) Mol Cell Neurosci 8, 389-404; and U.S. patent application 20020155173.